WO2002049688A1

WO2002049688A1 - Bio-compatible polymeric materials

Info

Publication number: WO2002049688A1
Application number: PCT/GB2001/005583
Authority: WO
Inventors: Brian Wilson; John Neil Devine
Original assignee: Victrex Manufacturing Limited
Priority date: 2000-12-21
Filing date: 2001-12-18
Publication date: 2002-06-27
Also published as: GB0031210D0; AU2002222245A1

Abstract

A bio-compatible polymeric material for use in medical applications is described wherein said material comprises a polymer, for example polyetheretherketone or polyetherketone in combination with an additive, for example hexadecylaniline or octadecanamide, wherein bio-compatible moieties are associated with moieties at the ends of chains of the additive.

Description

BIO-COMPATIBLE POLYMERIC MATERIALS

This invention relates to bio-compatible polymeric materials and particularly, although not exclusively, provides a bio-compatible polymeric material, a method of producing such a material and the use of such a material in medical treatment, for example in a prosthesis.

Much research is being directed to the provision of materials to meet the growing need for prosthetic devices such as orthopaedic, dental or maxillόfacial implants. For example, nearly half a million patients receive bone implants each year in the US with the majority being artifical hip and knee joints made from titanium or colbalt-chrome alloys. However, these materials are too stiff leading to bone resorption, loosening of the implant and, consequently, have lifetimes of less than 10 years. Additionally, medical devices or prostheses such as pacemakers, vascular grafts, stents, heart valves, catheters and dental implants that contact body tissues or fluids of living persons or animals have been developed and used clinically.

A major problem with medical devices such as those described is the susceptibility to foreign body reaction and possible rejection. Consequently, it is of great interest to the medical industry to develop materials from which medical devices can be made which are less prone to adverse biological reactions that typically accompany introduction of medical devices into humans or animals.

It is an object of the present invention to address the above described problems . According to a first aspect of the invention, there is provided a bio-compatible polymeric material for use in medical applications, wherein said material comprises a polymer and an additive, wherein bio-compatible moieties are associated with moieties at the ends of chains of the additive.

In the scientific literature there is inconsistency in the use of descriptions such as "bio-compatible", bio- active" and "bio-materials" . In the context of the present specification, the term "bio-compatible" has generally been used to refer to a material which is compatible with use in medical applications, for example by not being toxic or otherwise harmful to living materials. It also encompasses materials which have a biological or physiological effect when associated with living materials.

"Bio-compatible moieties" referred to herein suitably refer to moieties which are compatible with use in medical applications, for example by not being toxic or otherwise harmful to living material. Such bio-compatible moieties may be arranged to bond (for example to form ionic or covalent bonds) or otherwise interact with materials present in human or animal bodies in order to improve their integration and acceptance by such bodies .

Except where otherwise stated, throughout this specification, any alkyl, akenyl or alkynyl moiety suitably has up to 8, preferably up to 6, more preferably up to 4, especially up to 2, carbon atoms and may be of straight chain or, where possible, of branched chain structure. Generally, methyl and ethyl are preferred alkyl groups and C₂ alkenyl and alkynyl groups are preferred.

Except where otherwise stated in this specification, optional substituents of an alkyl, alkenyl or alkynyl group may include halogen atoms, for example fluorine, chlorine, bromine and iodine atoms, and nitro, cyano, alkoxy, hydroxy, a ino, alkylamino, sulphinyl, alkylsulphinyl, sulphonyl, alkylsulphonyl, amido, alkylamido, alkoxycarbonyl, haloalkoxycarbonyl and haloalkyl groups. Preferably, optionally substituted alkyl, alkenyl or alkynyl groups are unsubstituted.

Preferably, said bio-compatible polymeric material has improved or enhanced bio-compatibility compared to said polymer in the absence of said additive having bio- compatible moieties associated therewith. Preferably, said additive when associated with bio-compatible moieties has improved or enhanced bio-compatibility compared to said additive in the absence of associated said moieties.

Bio-compatible moieties suitably include moieties arranged to reduce adverse biological reactions when the polymeric material is introduced into (or otherwise associated with) a human or animal body. For example, adverse biological reactions associated with introduction into a human or animal body of said polymer having said bio-compatible moieties may be less compared to use of the same polymer but which does not include associated bio- compatible moieties. Preferably, said polymer has phenyl moieties; carbonyl or sulphone moieties; and ether or thioether moieties in the polymer backbone.

Preferably, said polymer has a moiety of formula

and/or a moiety of formula

and/or a moiety of formula

wherein the phenyl moieties in units I, II, and III are independently optionally substituted and optionally cross- linked; and wherein m,r,s,t,v,w and z independently represent zero or a positive integer, E and E' independently represent an oxygen or a sulphur atom or a direct link, G represents an oxygen or sulphur atom, a direct link or a -0-Ph-O- moiety where Ph represents a phenyl group and Ar is selected from one of the following moieties (i)*, (i)**, (i) to (x) which is bonded via one or more of its phenyl moieties to adjacent moieties

In (i)* , the middle phenyl may be 1,4- or 1,3- substituted.

Unless otherwise stated in this specification, a phenyl moiety may have 1,4- or 1,3-, especially 1,4-, linkages to moieties to which it is bonded.

Said polymer may include more than one different type of repeat unit of formula I; more than one different type of repeat unit of formula II; and more than one different type of repeat unit of formula III. Preferably, however, only one type of repeat unit of formula I, II and/or III is provided.

Said moieties I, II and III are suitably repeat units. In the polymer, units I, II and/or III are suitably bonded to one another - that is, with no other atoms or groups being bonded between units I, II, and III.

Where the phenyl moieties in units I, II or III are optionally substituted, they may be optionally substituted by one or more halogen, especially fluorine and chlorine, atoms or alkyl, cycloalkyl or phenyl groups. Preferred alkyl groups are Cχ_ιo, especially Cι_₄, alkyl groups. Preferred cycloalkyl groups include cyclohexyl and multicyclic groups, for example adamantyl.

Another group of optional substituents of the phenyl moieties in units I, II or III include alkyls, halogens, CyF_2y+ι where y is an integer greater than zero, 0-R^g (where R^q is selected from the group consisting of alkyls, perfluoralkyls and aryls) , CF=CF₂, CN, N0₂ and OH. Trifluormethylated phenyl moieties may be preferred in some circumstances.

Preferably, said phenyl moieties are not optionally- substituted as described.

Where said polymer is cross-linked, it is suitably cross-linked so as to improve its properties. Any suitable means may be used to effect cross-linking. For example, where E represents a sulphur atom, cross-linking between polymer chains may be effected via sulphur atoms on respective chains. Preferably, said polymer is not optionally cross-linked as described.

Where w and/or z is/are greater than zero, the respective phenylene moieties may independently have 1,4- or 1,3-linkages to the other moieties in the repeat units of formulae II and/or III. Preferably, said phenylene moieties have 1,4- linkages.

Preferably, the polymeric chain of the polymer does not include a -S- moiety. Preferably, G represents a direct link.

Suitably, "a" represents the mole % of units of formula I in said polymer, suitably wherein each unit I is the same; "b" represents the mole % of units of formula II in said polymer, suitably wherein each unit II is the same; and "c" represents the mole % of units of formula III in said polymer, suitably wherein each unit III is the same. Preferably, a is in the range 45-100, more preferably in the range 45-55, especially in the range 48-52. Preferably, the sum of b and c is in the range 0-55, more preferably in the range 45-55, especially in the range 48- 52. Preferably, the ratio of a to the sum of b and c is in the range 0.9 to 1.1 and, more preferably, is about 1. Suitably, the sum of a, b and c is at least 90, preferably at least 95, more preferably at least 99, especially about 100. Preferably, said polymer consists essentially of moieties I, II and/or III.

Said polymer may be a homopolymer having a repeat unit of general formula

or a homopolymer having a repeat unit of general formula

or a random or block copolymer of at least two different units of IV and/or V

wherein A, B, C and D independently represent 0 or 1 and E,E' ,G,Ar,m,r,s, t,v,w and z are as described in any statement herein.

As an alternative to a polymer comprising units IV and/or V discussed above, said polymer may be a homopolymer having a repeat unit of general formula

or a homopolymer having a repeat unit of general formula

or a random or block copolymer of at least two different units of IV* and/or V*, wherein A, B, C, and D independently represent 0 or 1 and E, E', G, Ar, m, r, s, t, v, w and z are as described in any statement herein.

Preferably, m is in the range 0-3, more preferably 0-2, especially 0-1. Preferably, r is in the range 0-3, more preferably 0-2, especially 0-1. Preferably t is in the range 0-3, more preferably 0-2, especially 0-1. Preferably, s is 0 or 1. Preferably v is 0 or 1. Preferably, w is 0 or 1. Preferably z is 0 or 1.

Preferably, said polymer is a homopolymer having a repeat unit of general formula IV.

Preferably Ar is selected from the following moieties (xi)*, (xi)**,(xi) to (xxi) :

In (xi)*, the middle phenyl may be 1,4- or 1,3- substituted. Preferably, (xv) is selected from a 1,2-, 1,3-, or a 1,5- moiety; (xvi) is selected from a 1,6-, 2,3-, 2,6- or a

2.7- moiety; and (xvii) is selected from a 1,2-, 1,4-, 1,5-

1.8- or a 2,6- moiety.

One preferred class of polymers does not include any moieties of formula III, but suitably only includes moieties of formulae I and/or II . Where said polymer is a homopolymer or random or block copolymer as described, said homopolymer or copolymer suitably includes a repeat unit of general formula IV. Such a polymer may, in some embodiments, not include any repeat unit of general formula V.

Suitable moieties Ar are moieties (i)*, (i) , (ii) , (iii) and (iv) and, of these, moieties (i)*, (i) and (iv) are preferred. Other preferred moieties Ar are moieties (xi)*, (xii) , (xi) , (xiii) and (xiv) and, of these, moieties (xi)*, (xi) and (xiv) are especially preferred.

An especially preferred class of polymers are polymers which consist essentially of phenyl moieties in conjunction with ketone and/or ether moieties. That is, in the preferred class, the polymer does not include repeat units which include -S-, -S0₂- or aromatic groups other than phenyl. Preferred polymers of the type described include:

(a) a polymer consisting essentially of units of formula IV wherein Ar represents moiety (iv) , E and E' represent oxygen atoms, m represents 0, w represents 1, G represents a direct link, s represents 0, and A and B represent 1 (i.e.polyetheretherketone) . (b) a polymer consisting essentially of units of formula IV wherein E represents an oxygen atom, E ' represents a direct link, Ar represents a moiety of structure (i) , m represents 0, A represents 1, B represents 0 (i.e. polyetherketone);

(c) a polymer consisting essentially of units of formula IV wherein E represents an oxygen atom, Ar represents moiety (i)*, m represents 0, E' represents a direct link, A represents 1, B represents 0, (i.e. polyetherketonketone) ;

(d) a polymer consisting essentially of units of formula IV wherein Ar represents moiety (i) , E and E' represent oxygen atoms, G represents a direct link, m represents 0, w represents 1, r represents 0, s represents 1 and A and B represent 1. (i.e. polyetherketoneetherketoneketone) .

(e) a polymer consisting essentially of units of formula IV, wherein Ar represents moiety (iv) , E and E' represents oxygen atoms, G represents a direct link, m represents 0, w represents 0, s, r, A and B represent 1 (i.e. polyetheretherketoneketone) .

Of the aforesaid, the polymers described in (a) and (b) are preferred, with the polymer described in (a) being especially preferred.

Said bio-compatible moieties are preferably associated with the surface of said bio-compatible polymeric material and, suitably, do not substantially penetrate the bulk of the material. Preferably, in a bio-compatible polymeric material, moieties at the ends of chains of said additive within the bulk thereof are different compared to moieties (i.e. bio-compatible moieties) associated with ends of chains of said additive at the surface of the bio- compatible polymeric material. Thus, the concentration of bio-compatible moieties at a surface of said bio- compatible polymeric material is preferably greater than the concentration in the bulk of said material . Consequently, said bio-compatible moieties are suitably associated with chain ends of said additive which are at the surface of the polymer. The concentration of chain end moieties at the surface may be greater than the concentration in the bulk. Chain ends of said additive below the surface of the polymeric material preferably do not include associated bio-compatible moieties.

Said additive suitably makes up at least 0.1 wt%, preferably at least 0.3 wt%, more preferably at least 0.5 wt%, especially at least 0.7 wt% of said bio-compatible polymeric material . The amount of said additive in said bio-compatible polymeric material may be less than 5 wt%, preferably less than 4 wt%, more preferably less than 3 wt%, especially less than 2 wt%.

A moiety at the end of a chain of the additive may be situated at the end of a chain (which could be a branched or straight chain but is preferably a straight chain) which has at least 4, suitably at least 6, preferably at least 8, more preferably at least 10, especially at least 12 chain atoms, which are preferably carbon atoms. Said moiety may be situated at the end of a chain (preferably a carbon atom chain) which has at least 4, suitably at least 6, preferably at least 8, more preferably at least 10, especially at least 12 chain atoms, which are preferably carbon atoms in a line (i.e. the number of chain atoms referred to does not include any chain atoms which may form branches extending from the atoms which are in a line) . Said additive may include chain atoms which form branches extending from atoms in a line but preferably does not include branches . Where said additive includes branches, preferably the branches do not include moieties which are, or are arranged to be, associated with the bio- compatible moieties of the bio-compatible material. Said moiety at . the end of a chain of said additive is preferably situated at an end of a line of atoms (preferably a line of carbon atoms) which is the longest line of atoms of said additive.

Said additive suitably includes less than 4, preferably less than 3, more preferably less than 2, moieties associated with bio-compatible moieties. Said additive preferably includes a single moiety associated with a bio-compatible moiety and preferably includes no other moiety capable of being associated with bio- compatible moieties.

Said additive is preferably not a polymer having moieties I, II and/or III as described above for said polymer. Preferably, said additive is not any type of polymer.

Said additive is preferably an optionally-substituted hydrocarbon, more preferably an optionally-substituted alkane, alkene, or alkyne especially an optionally- substituted alkane. Said additive may have at least 6, suitably at least 8, preferably at least 10, more preferably at least 12, especially at least 14 carbon atoms. The number of carbon atoms may be less than 30, suitably less than 25, preferably less than 20, more preferably less than 18.

The invention extends to a bio-compatible polymeric material for use in medical applications, wherein said material comprises a polymer and an additive, wherein a surface of said material includes said additive, with bio- compatible moieties being associated with moieties at the end of chains of the additive and wherein the bulk of said polymeric material does not include associated bio- compatible moieties. Thus, preferably, the concentration of bio-compatible moieties at the surface of said polymeric material is greater than the concentration in the bulk.

Said polymer may include fluorine atoms associated with its chain ends.

Since a major amount of said additive is suitably present only at or adjacent a surface of said bio- compatible polymeric material and is present at a small fraction of the total weight of said polymer, the existence of said additive and/or associated bio- compatible moieties may have limited effect on the bulk properties of said polymer compared to said polymer in the absence of said additive and/or associated bio-compatible moieties.

The glass transition temperature (T_g) of said polymer, suitably the bulk thereof, (in the absence of said additive and/or associated bio-compatible moieties) may be at least 135°C, suitably at least 150°C, preferably at least 154°C, more preferably at least 160°C, especially at least 164°C. In some cases, the Tg may be at least 170°C, or at least 190°C or greater than 250°C or even 300°C.

Said polymer, suitably the bulk thereof, (in the absence of said additive and/or associated bio-compatible moieties) may have an inherent viscosity (IV) of at least 0.1, suitably at least 0.3, preferably at least 0.4, more preferably at least 0.6, especially at least 0.7 (which corresponds to a reduced viscosity (RV) of least 0.8) wherein RV is measured at 25°C on a solution of the polymer in concentrated sulphuric acid of density 1.84gcm^"3, said solution containing lg of polymer per 100cm^"3 of solution. IV is measured at 25°C on a solution of polymer in concentrated sulphuric acid of density 1.84gcm³, said solution containing 0. lg of polymer per 100cm³ of solution.

The measurements of both RV and IV both suitably employ a viscometer having a solvent flow time of approximately 2 minutes .

The main peak of the melting endotherm (Tm) for said polymer, suitably the bulk thereof, (if crystalline) may be at least 300°C.

Preferably, said polymer, suitably the bulk thereof,

(in the absence of said additive and/or associated bio- compatible moieties) has at least some crystallinity or is crystallisable. The existence and/or extent of crystallinity in a polymer is preferably measured by wide angle X-ray diffraction, for example as described by Blundell and Osborn (Polymer 24, 953, 1983) . Alternatively, crystallinity may be assessed by Differential Scanning Calorimetry (DSC) .

Said polymer, suitably the bulk thereof, (in the absence of said additive and/or associated bio-compatible moieties) may have a number average molecular weight in the range 2000-80000. Preferably said molecular weight is at least 14,000. The molecular weight may be less than 60,000.

Said bio-compatible polymeric material may include a blend of polymers which comprises said polymer along with another polymer which is preferably a different type of polymer compared to said polymer but may otherwise have any feature of said polymer described here. For example, it may include moieties I and/or II and/or III.

Said bio-compatible polymeric material suitably has a tensile strength (according to ISO R527) of at least 80, preferably at least 90, especially at least 95 MPa. The tensile strength may be less than 360, suitably less than

250, preferably less than 140 MPa. It preferably has an elongation at break (according to ISO R527) of at least 40, preferably at least 50%. It preferably has a tensile modulus (according to ISO R527) of greater than 2.5, preferably greater than 3, especially greater than 3.5

GPa. The tensile modulus may be less than 40, suitably less than 30, preferably less than 20, more preferably less than 10 GPa. It preferably has a flexural strength

(according to ASTM D695) of at least 100, more preferably at least 110, especially at least 115 MPa. The flexural strength may be less than 650, preferably less than 400, more preferably less than 260, especially less than 200 MPa. It preferably has a flexural modulus (according to ISO R178) of at least 3, preferably at least 3.5, especially at least 4 GPa. The flexural modulus may be less than 60, suitably less than 25, preferably less than 20 especially less than 10 GPa. Advantageously, the aforementioned properties can be adjusted by appropriate selection of polymers and/or any reinforcement means included in said support material to suit particular applications. For example, a continuous carbon fibre polyetheretherketone may typically have a tensile strength of about 350 MPa, a tensile modulus of 36 GPa, an elongation of 2%, a flexural modulus of 50 GPa and a flexural strength of 620 MPa. A polyaryetherketone with 30% of high performance fibres typically may have a tensile strength of 224 MPa, a tensile modulus of 13 GPa, a tensile elongation of 2%, a flexural modulus of 20 GPa and a flexural strength of 250 MPa.

Said bio-compatible polymeric material may include one or more fillers for providing desired properties. Said material preferably incorporates an X-ray contrast medium. Fillers and/or said X-ray contrast medium is/are preferably distributed substantially uniformly throughout said material.

Where an X-ray contrast medium is provided it suitably comprises less than 25wt%, preferably less than 20wt%, more preferably less than 15wt%, especially less than 10wt% of said bio-compatible material. Where it is provided, at least 2wt% may be included. Preferred X-ray contrast mediums are particulate and preferably are inorganic. They preferably have low solubility in body fluids. They preferably also have a sufficient density compared to that of the polymer to create an image, if a compounded mixture of the polymer and contrast medium are X-ray imaged. Barium sulphate and zirconium oxide are examples. Said particulate material is suitably physically held in position by entrapment within the polymer.

Preferably, said bio-compatible polymeric material includes a major amount of said polymer, especially one having moieties I, II and/or III, described according to said first aspect.

In the context of this specification, a "major" amount may mean greater than 50 wt%, suitably greater than 65 wt%, preferably greater than 80 wt%, more preferably greater than 95 wt%, especially greater than 98 wt% of the referenced material is present relative to the total weight of relevant material present .

Where said bio-compatible polymeric material comprises a blend, said blend preferably includes at least two polymers of a type according to said first aspect. For example, said at least two polymers preferably include moieties I, II and/or III as described above. A said blend preferably includes a major amount of higher (or the highest) number average molecular weight polymer. Said bio-compatible polymeric material preferably includes a major amount of a higher molecular weight polymer.

A said bio-compatible moiety may be selected from an anticoagulant agent such as heparin and heparin sulfate, an antithrombotic agent, a clotting agent, a platelet agent, an anti-inflammatory agent, an antibody, an antigen, an immunoglobulin, a defence agent, an enzyme, a hormone, a growth factor, a neurotransmitter, a cytokine, a blood agent, a regulatory agent, a transport agent, a fibrous agent, a protein such as avidin, a glycoprotein, a globular protein, a structural protein, a membrane protein and a cell attachment protein, a peptide such as a glycopeptide, a structural peptide, a membrane peptide and a cell attachment peptide, a proteoglycan, a toxin, an antibiotic agent, an antibacterial agent, an antimicrobial agent such as pencillin, ticarcillin, carbenicillin, ampicillin, oxacillian, cefazolin, bacitracin, cephalosporin, cephalothin, cefuroxime, cefoxitin, norfloxacin, perfloxacin and sulfadiazine, hyaluronic acid, a polysaccharide, a carbohydrate, a fatty acid, a catalyst, a drug, biotin, a vitamin, a DNA segment, a RNA segment, a nucleic acid, a nucleotide, a polynucleotide, a nucleoside, a lectin, a ligand and a dye (which acts as a biological ligand) , a radioisotope, a chelated radioisotope, a chelated metal, a metal salt, a sulphonic acid or salt thereof, a steroid, a non-steriod, a non- steroidal anti-inflammatory, an analgesic, an anti- histamine, a receptor binding agent, a chemotherapeutic agent, a hydrophilic polymer, (e.g. poly (ethylene glycol) (PEG), poly(ethylene oxide) (PEO) , ethylene oxide- propylene oxide block co-polymers, poly (N-vinyl-2- pyrrolidone) (PNVP) , poly (2-hydroxyethyl methacrylate)

(pHEMA) , HEMA co-polymers, poly (vinyl alcohol) (PVA) , polyacrylamide, its derivatives, poly(methyl methacrylate)

(PMMA) , suitably having a PEG chain on each of the side groups, polysiloxanes (e.g. polydimethylsiloxanes (PDMS)), ionic water-soluble polymers like poly(acrylic acid) (PAAc) ) and a polyurethane . Examples of some of the aforesaid are provided in US5958430, US5925552, US5278063 and US5330911 and the contents of the aforementioned specifications are incorporated herein by reference.

In one embodiment, said bio-compatible moieties may comprise bone morphogenic protein (BMP) as described in US4563489 and patents cited therein and the contents of the aforesaid are incorporated herein. Said BMP may be provided in combination, for example in admixture, with a physiologically acceptable biodegradable organic polymer and said biodegradable polymer may be associated with moieties at the ends of chains of the additive, for example by being covalently bonded to moieties at the ends of chains. Thus, in this case, the combination of said biodegradable polymer and BMP defines said bio-compatible moieties. Said biodegradable polymer is preferably a biodegradable polylactic acid; or alternatively, other physiologically acceptable biodegradable organic polymers which are structurally equivalent to polylactic acid can be used as the delivery system for BMP. Examples include poly(hydroxy organic carboxylic acids) e.g. poly(hydroxy aliphatic carboxylic acids) , polyglycollic acid, polyglactin, polyglactic acid and poly adonic acids.

In another embodiment, said bio-compatible moieties may be selected from inorganic crystalline structures, inorganic amorphous structures, organic crystalline structures and organic amorphous structures . Preferred bio-compatible moieties are phosphorous based ceramics, for example calcium-phosphorous ceramics. Phosphates in general are suitable but calcium phosphates and calcium apatite are preferred. Especially preferred is hydroxyapatite, a synthetic Ca-P ceramic. Linking moieties, for example linking atoms or groups may extend between said additive and said bio-compatible moieties. Said linking moieties may be covalently bonded to moieties at the ends of chains of said additive. Said linking moieties may be covalently bonded to said bio- compatible moieties or may otherwise be associated with said moieties.

A said linking moiety may be associated with a single bio-compatible moiety or, alternatively, a said linking moiety may be associated with more than one bio-compatible moiety. Thus, said linking moiety may be mono-functional or multi-functional, for association with one or more bio- compatible moieties. Multi-functional linking moieties may be able advantageously to be associated with more bio- compatible moieties and may, therefore, provide a means to increase the concentration of bio-compatible moieties associated with said additive.

Whilst said bio-compatible moieties may be associated with moieties at the ends of chains of said additive by any suitable means, for example covalent bond(s), hydrogen bond(s) , encapsulation in a matrix which is bonded to or otherwise interacts with said end groups, or ionic interaction (s) , it is preferred that there are covalent bonds between the bio-compatible moieties and said additive or there are ionic interactions between said bio- compatible moieties and said additive.

An additive/bio-compatible moiety arrangement may be represented by the formula:

AC-EG' .BM' where AC represents a said additive chain which suitably is a low molecular weight chain, suitably with Mn ranging from 250-3000 which is suitably arranged to anchor the additive into the polymer; EG¹ represents a moiety at the end of said chain; and BM¹ represents a bio-compatible moiety.

EG¹ may include said aforementioned linking moiety.

In some cases, EG' and EG' .BM¹ may be the same, for example where an end group of the additive is itself bio- compatible. A -S0₃H end group may fall into this category. Preferably, however, EG' and EG' .BM' represent different moieties.

The bond between AC and EG' is suitably a covalent bond. The interaction between EG' and BM' may be by any suitable means as described above. The interaction is preferably by means of a covalent bond or an ionic interaction.

According to a second aspect of the invention, there is provided a method of making a bio-compatible polymeric material for use in medical applications, the method including the step of causing bio-compatible moieties to become associated with moieties at the ends of chains of an additive, wherein said additive is mixed with a polymer.

Preferably, the method includes the step of blending said polymer and said additive, suitably at an elevated temperature, suitably at greater than 200°C, preferably at greater than 300°C, more preferably at greater than 325°C, especially at greater than 350°C. The blending is preferably undertaken using a high shear mixer.

The amount of said additive in said blend may be at least 0.2 wt%, suitably at least 0.4 wt%, preferably at least 0.6 wt%, more preferably at least 0.8 wt%. The amount may be less than 5 wt%, suitably less than 4 wt%, preferably less than 3 wt%, more preferably less than 2 wt%, especially less than 1.5 wt%.

The method preferably includes the step of treating a mixture of the polymer and the additive so that, when in solid form, the concentration of additive at a surface of the solid is greater than in the bulk of the solid. Thus, the method preferably includes treating the mixture to cause migration of additive to a surface of a solid. Said additive preferably includes a functional group at the end of a chain thereof, wherein preferably said functional group facilitates the migration of the additive to a surface of the solid. To this end, said functional group is preferably relatively incompatible with the polymer which suitably forms a major part of the bio-compatible material. By way of example, a mixture of polymer and additive may be treated by injection moulding. In the melt, the additive should be evenly distributed through the bulk of the polymer. However, as the polymer begins to cool additive molecules, suitably having relatively short chains, migrate to the surface.

A said functional group of said additive may be post- functionalised to enable association with bio-compatible moieties. However, said functional groups need not be. The method preferably includes the step of treating a mixture of said polymer and said additive with a material for providing bio-compatible moieties (hereinafter "BCM material") arranged to provide bio-compatible moieties for association with moieties at the ends of chains of the additive. Said BCM material may be arranged to provide any of the bio-compatible moieties described herein. Said mixture comprising said polymer and said additive may be provided as a solid. Suitably, said bio-compatible moieties are caused to become associated with a surface of said solid, preferably with moieties at the ends of chains of the additive present at a surface of said solid. Said solid is preferably shaped so as to represent at least a part of a device for use in medical applications. For example, said device may be a component of an implant for a human or animal body, for example an orthopaedic or dental implant or vascular graft. Said solid may be provided in a desired shape by any suitable means, for example by injection or compression moulding or by film formation techniques or extrusion. Thus, preferably, after association with said bio-compatible moieties, the bio-compatible polymeric material is not engineered or otherwise treated in a manner which may result in substantial depletion of the bio-compatible moieties associated with its surface.

Association of bio-compatible moieties with said moieties at the ends of chains may be effected in any suitable way which will depend on the nature of the BCM material and/or the identity of moieties at the ends of chains of the additive. In some embodiments, the method may include causing covalent bond formation between the additive and said bio-compatible moieties. In other embodiments, association of the additive and bio- compatible moieties may be effected by other means, for example by ionic interactions.

Where EG' and EG' .BM¹ represent different moieties, the method may include the step of treating an additive of general formula

AC-EG

wherein AC represents a said additive chain and EG represents a moiety at the end of the chain with a material (BM) arranged to supply a bio-compatible material (BM¹) thereby to produce an additive bio-compatible moiety arrangement represented by the formula AC-EG' .BM' as described above wherein EG' .BM' represents an association between a moiety at the end of a chain of the additive and the bio-compatible material, wherein EG' represents a residue of end group EG or may represent EG, for example where there is no covalent bond formation between EG¹ and BM' ; and BM' represents a residue of bio-compatible material BM or may represent BM where there is no covalent bond formation between EG' and BM' .

EG may include any suitable functional groups arranged to become associated with suitable functional groups provided on BM. For example EG may include a functional group selected from the following: -OH, -CHO, -NR¹⁰ ₂, preferably -NH₂ or -NHR¹⁰, -SH, -CONH₂, -CONHR¹⁰, -COOH, -COC1 or -COOR¹⁰ group, a halogen atom, especially a fluorine, chlorine, bromine or iodine atom, -N0₂, -S0₃M, -SOaR¹¹, -S0₂NHR¹⁰, -SO₂NR¹⁰ ₂ or -COOM groups, an anhydride, an epoxide, a cyanate, -CN, an isocyanate, a carbon-carbon double bond, for example a group -CR¹⁰=CR¹⁰ ₂ or a (C_o-Cι₀alk) acrylate (wherein "alk" refers to an alkyl group) such as -COOC(CH₃)CH₂ and -COOCHCH₂, a carbon-carbon triple bond, for example a group -CR¹⁰ or an azide, wherein R¹⁰ represents a hydrogen atom or an optionally substituted alkyl group, wherein M represents a hydrogen atom or an alkali metal and R¹¹ represents a halogen, especially a chlorine, atom.

BM may include any suitable functional group that is arranged to become associated with functional groups included in EG and may be selected from any of the functional groups referred to above for EG provided that a selected functional group provided by EG is capable of becoming associated with, suitably reacting, with a selected functional group provided by BM.

In some cases BM may be provided by reaction of EG with more than one functional group. For example a BM' may represent a polyurethane which may be prepared when EG provides a hydroxy group and BM provides a diisocyanate and a diol; or wherein EG provides an isocyanate group and BM provides a diisocyanate and a diol. In both cases, two different compounds BM may be used.

In some cases, BM may be provided by a monomer or monomers having a functional group arranged to react with EG and being arranged to polymerise to provide a polymeric moiety BM' .

In one embodiment, EG may be ionic in character, for example it may be -COOM or -S0₃M and such a group may be arranged to ionically associate with an ionic moiety provided by BM.

In other embodiments, an amide bond may be formed between EG and BM.

In some cases, said group EG may be multi-functional, thereby enabling it to associate with a plurality of bio- compatible moieties. For example, multi-functionality may be provided by dendritic or hyperbranched end groups.

The polymer comprising moieties I, II and/or III may be prepared as described in WO00/15691 and/or EP1879, the contents of which are incorporated herein by reference. The aforementioned document describes processes for preparing the polymers which are generally nucelophilic processes. Nonetheless, electrophilic processes can be used, by analogy to the processes described in US 5081215, US4808693, US4708448 and US5081215.

According to a third aspect of the present invention, there is provided a device for use in medical applications, wherein said device comprises a bio- compatible polymeric material according to said first aspect or made in a method according to said second aspect .

Said device is preferably a prosthetic device, for example an implant such as an orthopaedic, dental or maxillofacial implant or a component thereof; or a device, for example a catheter, which is arranged to be temporarily associated with a human or animal body. Said device is preferably a prosthetic device as described. An orthopaedic device may be an implant for a body joint, for example a hip or knee joint or spine fusion device.

A said device may include a part or parts made out of said bio-compatible polymeric material and a part or parts made out of other materials. Suitably, however, said device includes at least 50wt%, preferably at least 65wt%, more preferably at least 80wt%, especially at least 95wt% of said bio-compatible polymeric material. In some embodiments said device may consist essential of said bio- compatible polymeric material .

According to a fourth aspect, there is provided a method of making a device according to the third aspect, the method comprising: forming a material into a shape which represents or is a precursor of a device or a part of a device for use in medical applications wherein said material comprises a polymer and an additive wherein moieties at the ends of chains of the additive are arranged to be associated with bio-compatible moieties; and treating material in said shape (preferably the surface thereof) thereby to cause bio-compatible moieties to associate with said moieties at the ends of chains of the additive (preferably moieties present at or near the surface of said material) .

The invention extends to the use of a bio-compatible polymeric material comprising a polymer and an additive, wherein bio-compatible moieties are associated with moieties at the ends of chains of the additive in the manufacture of a device for use in a medical treatment, for example in surgery. Any feature of any aspect of any invention or embodiment described herein may be combined with any feature of any aspect of any other invention or embodiment described herein.

Specific embodiments of the invention will now be described, by way of example.

All chemicals referred to herein were used as received from Sigma-Aldrich Chemical Company, Dorset, U.K., unless otherwise stated.

Specific embodiments of the invention will now be described, by way of example.

Example 1 - Fluorine-terminated polyetheretherketone

A 250 ml. 3-necked, round-bottomed flask with a stirrer/stirrer guide, nitrogen inlet and outlet and a thermocouple was charged with 4,4' -difluorobenzophenone

(22.15g, 0.1015 mole), hydroquinone (ll.Olg, 0.10 mole) and diphenylsulphone (60. Og) and purged with nitrogen for over 1 hour. The contents were then heated under a nitrogen blanket to between 140 and 150°C to form an almost colourless solution. While maintaining a nitrogen blanket, dried sodium carbonate (10.60g, 0.10 mole) and potassium carbonate (0.28g, 0.002 mole) was added. The temperature was raised to 175°C, held for 60 min; heated to 200°C, held for 30 mins; heated to 250°C, held for 30 mines; heated to 300°C and held for 120 mins.

The reaction mixture was allowed to cool, milled and washed with acetone and water. The resulting polymer was dried in an air oven at 120°C. The polymer had Inherent Viscosity (IV) of 1.15. IV is measured at 25°C on a solution of polymer in concentrated sulphuric acid of density 1.84 gem^"3, said solution containing O.lg of polymer per 100cm³ of solution. A Melt Viscosity (MV) of 0.39kNsm^"2 measured at 400 °C on a ram extruder at a shear rate of 10000 s^"1. Tg = 142°C and Tm = 342°C.

Example 2 - Blending of polyetheretherketone with hexadecanesulphonic acid sodium salt

The polymer of Example 1 was blended with

1-hexadecanesulphonic acid sodium salt (1% w/w) at 360°C in a Brabender high shear mixer which was continuously purged with nitrogen. The mixture was compression moulded to produce a film 5 cm x 5 cm x 125μm.

During compression moulding, the sodium salt migrates to the surface and this can be shown by determining the level of sulphur on the surface of the blend (e.g. by X- ray. photoelectron spectroscopy (XPS) ) and comparing it to the polymer of Example 1 in the absence of any additive.

Example 3- Conversion of surface sulphonic acid sodium salt to sulphonic acid

The polymer film of Example 2 was placed in a 250ml flanged flask fitted with a reflux condenser, a magnet follower and a nitrogen inlet and outlet and with charged 0.1M hydrochloric acid (120ml) . Under a nitrogen atmosphere and with continuous stirring the contents were heated to 50°C for 6 hours. The reaction mixture was allowed to cool to room temperature, the sample was removed, washed with deionised water until the pH was neutral and dried.

Example 4 - Calcium Phosphate Deposition on a sulphonic acid and sodium sulphonate-surface modified polyetheretherketone .

A supersaturated calcium phosphate solution containing 5mM CaCl₂, l,5mM KH₂P0₄ and 1.5mM Na₂HP0₄ was prepared by mixing 0.1M Na₂HP0₄ solution (1.5ml) and deionised water (92ml), followed by the slow addition of 0.1M CaCl₂ solution (5.0ml). The solution was stirred for 3 minutes and film samples, from Examples 2 and 3, were immersed in the solution for 1 hour. The films were washed with deionised water and blown dry with nitrogen. The process can be repeated several times to achieve a desired thickness of deposited calcium phosphate.

Example 5 - Blending of polyetheretherketone with hexadecylaniline.

The polymer of Example 1 was blended with

4-hexadecylaniline (1% w/w) (Aldrich) at 360°C in a

Brabender high shear mixer which was continuously purged with nitrogen. The mixture was compression moulded to produce a film 5 cm x 5 cm x 125 μm.

Example 6 - Reaction of amino surface modified polyetheretherketone with the peptide GRGDS.

The film of the surface modified polyetheretherketone of Example 5 was placed in a 250ml round-bottomed flask fitted with a magnetic follower and a nitrogen inlet and outlet and containing N,N-dimethylacetamide (60ml) , and disuccinimidylsuberate (150mg) . The contents were stirred under an atmosphere of nitrogen at room temperature for 2 hrs. The specimen was removed, washed with ether and dried in vacuo for lOhrs at 50°C. The dried sample was stirred at 20°C for 24 hr under an atmosphere of nitrogen in a solution of the peptide GRGDS (80mg) in an aqueous buffer solution (40ml), pH 9. The functionalised polyetheretherketone was washed successively with the buffer solution and ether.

Example 7 - Blending of Polyetheretherketone with Octadecanamide

The polymer of Example 1 was blended with octadecanamide (1% w/w) at 360°C in a Brabender high shear mixer which was continuously purged with nitrogen. The mixture was compression moulded to produce a film 5 cm x 5cm x 125μm.

Example 8 - Hydrolysis of the amide group of a modified polyetheretherketone film

A film from Example 7 was placed in a 250ml round bottomed flask fitted with a reflux condenser. To the flask was added 80ml of a 10% aqueous sodium hydroxide and 15ml of ethanol in order to facilitate complete hydrolysis of the amide to the carboxylic acid. The solution was heated to reflux for 12-24 hours in order to ensure complete hydrolysis. The solution was cooled and the film removed and placed in a solution of glacial acetic acid followed by washing with 2M HC1 and distilled water. The sample was dried at room temperature overnight. Example 9 - Reaction of surface modified polyetheretherketone containing carboxylic acid groups with the peptide GRGDS

A surface modified polyetheretherketone film from Example 8 was stirred at 10°C for 1 hr under an atmosphere of nitrogen in an aqueous solution of the water soluble carbodiimide, l-ethyl-3- (3-dimethylamino propyl) - carbodiimide) (8g) dissolved in buffer at pH 4.5 (0.1M 2- (N-morpholino) ethanesulphonic acid) (40ml). The sample of polyetheretherketone was removed and washed with buffer solution.

The sample was stirred at 20°C for 24 hr under an atmosphere of nitrogen in a solution of the peptide GRGDS (160mg) in phosphate-buffered saline solution (40ml) (Na₂HP0₄, 1.15g; KH₂P0₄, 0.2g; NaCl . 8g; KC1, 0.2g; MgCl_2/ O.lg; CaCl₂. 0. lg in 1 Litre of distilled water) . The functionalised polyetheretherketone was washed successively with phosphate buffer and distilled water. Each carboxyl group of the functionalised polyetheretherketone reacts with a separate peptide.

The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification (including any accompanying claims, abstract and drawings) , and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) , may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features .

The invention is not restricted to the details of the foregoing embodiment (s) . The invention extend to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings) , or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Claims

1. A bio-compatible polymeric material for use in medical applications, wherein said material comprises a polymer and an additive, wherein bio-compatible moieties are associated with moieties at the ends of chains of the additive .

2. A polymeric material according to claim 1, wherein said polymer has phenyl moieties; carbonyl or sulphone moieties; and ether or thioether moieties in the polymer backbone .

3. A polymeric material according to claim 1 or claim 2, wherein said polymer is selected from polyetheretherketone, polyetherketone, polyetherketoneketone, polyetherketoneetherketoneketone and polyetheretherketoneketone .

4. A polymeric material according to any preceding claim, wherein said polymer is selected from polyetheretherketone and polyetherketone .

5. A polymeric material according to any preceding claim, wherein said polymer is polyetheretherketone.

6. A polymeric material according to any preceding claim, wherein bio-compatible moieties are associated with the surface of said bio-compatible polymeric material and do not substantially penetrate the bulk of the material.

7. A polymeric material according to any preceding claim, wherein said additive makes up at least 0.1 wt% and less than 5 wt% of said bio-compatible polymeric material.

8. A polymeric material according to any preceding claim, wherein said additive is not a polymeric additive.

9. A polymeric material according to any preceding claim, wherein said additive is an optionally-substituted hydrocarbon.

10. A polymeric material according to any preceding claim, wherein said additive has at least 6 and less than 30 carbon atoms .

11. A bio-compatible polymeric material for use in medical applications, wherein said material comprises a polymer and an additive, wherein a surface of said material includes said additive, with bio-compatible moieties being associated with moieties at the ends of chains of the additive and wherein the bulk of said bio-compatible polymeric material does not include associated bio- compatible moieties.

12. A polymeric material according to any preceding claim, wherein said additive and said bio-compatible moieties define an additive/bio-compatible moiety arrangement represented by the formula:

AC-EG' .BM'

wherein AC represents a chain of said additive, EG¹ represents a moiety at the end of said chain; and BM" represents a bio-compatible moiety, wherein the bond between AC and EG' is a covalent bond.

13. A method of making a bio-compatible polymeric material for use in medical applications, the method including the step of causing bio-compatible moieties to become associated with moieties at the ends of chains of an additive, wherein said additive is mixed with a polymer.

14. A method according to claim 13, which includes the step of blending said polymer and said additive at an elevated temperature of greater than 200°C.

15. A method according to claim 13 or claim 14 which includes the step of treating a mixture of the polymer and the additive so that, when in solid form, the concentration of additive at a surface of the solid is greater than in the bulk of the solid.

16. A method according to claim 15, wherein said additive includes a functional group at the end of a chain thereof, wherein said functional group facilitates the migration of the additive to a surface of the solid.

17. A method according to any of claims 13 to 16, the method including the step of treating an additive of general formula:

AC-EG

wherein AC represents a said additive chain and EG represents a moiety at the end of the chain, with a material (BM) arranged to supply a bio-compatible material (BM¹) thereby to produce an additive/bio-compatible moiety arrangement represented by the formula AC-EG '.BM', wherein EG' .BM' represents an association between a moiety at the end of a chain of the additive and the bio-compatible material, wherein EG' represents a residue of end group EG or represents EG; and BM' represents a residue of bio- compatible material BM or represents BM.

18. A method according to claim 17, wherein EG includes a functional group selected from the following:

-OH, -CHO, -NR¹⁰ ₂, -SH, -CONH₂, -CONHR¹⁰, -COOH, -COC1 or -COOR¹⁰ group, a halogen atom, -N0₂, -S0₃M, -S0₂R^1:L, -S0₂NHR¹⁰, -SO₂NR¹⁰ ₂ or -COOM groups, an anhydride, an epoxide, a cyanate, -CN, an isocyanate, a carbon- carbon double bond, a carbon-carbon triple bond, or an azide, wherein R¹⁰ represents a hydrogen atom or an optionally substituted alkyl group, wherein M represents a hydrogen atom or an alkali metal and R¹¹ represents a halogen atom.

19. A method according to claim 17 or claim 18, wherein EG is ionic in character.

20. A method according to claim 17 or claim 18, wherein an amide bond is formed between EG and BM.

21. A device for use in medical applications, wherein said device comprises a bio-compatible polymeric material according to any of claims 1 to 12 or made in a method according to any of claims 13 to 20.

22. A method of making a device according to claim 21, comprising: forming a material into a shape which represents or is a precursor of a device or a part of a device for use in medical applications wherein said material comprises a polymer and an additive wherein moieties at the ends of chains of the additive are arranged to be associated with bio-compatible moieties; and treating material in said shape thereby to cause bio- compatible moieties to associate with said moieties at the ends of chains of the additive.

23. The use of a bio-compatible polymeric material comprising a polymer and an additive, wherein bio- compatible moieties are associated with moieties at the ends of chains of the additive in the manufacture of a device for use in a medical treatment .